This revised application, submitted in response to NIH PA-18-741 ?Secondary Analyses in Obesity, Diabetes, and Digestive and Kidney Diseases,? relates to the public health problem of childhood obesity, with a specific focus on the characterization, determinants and role of energy balance homeostasis-related brain circuitry in the human newborn. The proposal describes a comprehensive plan designed to advance neonatal MRI analytical methods, developmental systems neuroscience, and fetal programming of health and disease risk. The critical importance of the hypothalamic-limbic-cortical brain circuitry that regulates energy homeostasis is well established, and MRI-based measures of energy homeostasis-related brain circuits have been associated with obesity outcomes. However, it is unclear whether the observed differences in these brain regions and circuitry in obese relative to normal-weight individuals are a cause, consequence, or both, of the obese state. Moreover, relatively little is known about the developmental ontogeny of these brain regions and circuitry, particularly during the fetal period, and their prospective role in shaping propensity for childhood obesity. This project addresses this fundamental knowledge gap. We will develop novel measures and conduct analyses using newborn brain imaging and other data elements from 4 inter-linked NIH-funded projects on prenatal stress and fetal programming of brain development and infant body composition (R01 HD-060628; R01 MH-091351; R01 HD-065825; UG3 OD-023349). The importance of selecting the newborn brain as the starting time point derives from the logic that brain circuitry at this time could not yet have been influenced by postnatal factors such as diet/feeding, thereby enabling the study to disentangle the temporality of effects. In a recent position paper on the pathogenesis of obesity, the U.S. Endocrine Society emphasized the need to conceptualize obesity as a disorder of the energy homeostasis system and elucidate its underlying mechanisms and developmental influences. Towards this objective, and using a population of ~100 mother-infant dyads followed from early gestation through birth till 5 yrs age, we will integrate research aims that leverage the resources of these projects to advance our understanding of the origins of childhood obesity. Aim 1. Develop measures of energy homeostasis brain circuitry using anatomical, diffusion and functional MRI. Because such measures have not yet been established in newborn homeostasis circuitry, this aim will fulfill an important need in terms of not only scientific knowledge but also technical capability. Aim 2. Address the physiological relevance and clinical significance of these novel MRI-based newborn brain measures by testing the hypothesis that measures of the human newborn?s energy homeostasis brain circuitry are prospectively associated with infant adiposity and subsequent childhood obesity risk. Aim 3. Identify the prenatal (gestational biology) determinants of variation in the measures of newborn brain energy homeostasis circuitry that are associated with infant adiposity. Significance. By identifying the role and determinants of energy homeostasis-related brain circuitry in the human newborn, these findings will ultimately provide the basis for the subsequent development of strategies aimed at the primary prevention of childhood obesity.